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[This corrects the article DOI: 10.1371/journal.pcbi.1010551.].
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When deciding between options that do or do not lead to future choices, humans often choose to choose. We studied choice seeking by asking subjects to first decide between a choice opportunity or performing a computer-selected action, after which they either chose freely or performed the forced action. Subjects preferred choice when these options were equally rewarded, even deterministically, and traded extrinsic rewards for opportunities to choose. We explained individual variability in choice seeking using reinforcement learning models incorporating risk sensitivity and overvaluation of rewards obtained through choice. Model fits revealed that 28% of subjects were sensitive to the worst possible outcome associated with free choice, and this pessimism reduced their choice preference with increasing risk. Moreover, outcome overvaluation was necessary to explain patterns of individual choice preference across levels of risk. We also manipulated the degree to which subjects controlled stimulus outcomes. We found that degrading coherence between their actions and stimulus outcomes diminished choice preference following forced actions, although willingness to repeat selection of choice opportunities remained high. When subjects chose freely during these repeats, they were sensitive to rewards when actions were controllable but ignored outcomes-even positive ones-associated with reduced controllability. Our results show that preference for choice can be modulated by extrinsic reward properties including reward probability and risk as well as by controllability of the environment.
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Comportamento de Escolha , Motivação , Humanos , Reforço Psicológico , Recompensa , AtitudeRESUMO
PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.
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Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Humanos , Atrofia de Múltiplos Sistemas/terapia , Atrofia de Múltiplos Sistemas/diagnóstico , alfa-Sinucleína/metabolismo , Biomarcadores , CerebeloRESUMO
Recent functional imaging findings in humans indicate that creativity relies on spontaneous and controlled processes, possibly supported by the default mode and the fronto-parietal control networks, respectively. Here, we examined the ability to generate and combine remote semantic associations, in relation to creative abilities, in patients with focal frontal lesions. Voxel-based lesion-deficit mapping, disconnection-deficit mapping and network-based lesion-deficit approaches revealed critical prefrontal nodes and connections for distinct mechanisms related to creative cognition. Damage to the right medial prefrontal region, or its potential disrupting effect on the default mode network, affected the ability to generate remote ideas, likely by altering the organization of semantic associations. Damage to the left rostrolateral prefrontal region and its connections, or its potential disrupting effect on the left fronto-parietal control network, spared the ability to generate remote ideas but impaired the ability to appropriately combine remote ideas. Hence, the current findings suggest that damage to specific nodes within the default mode and fronto-parietal control networks led to a critical loss of verbal creative abilities by altering distinct cognitive mechanisms.
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Associação , Mapeamento Encefálico , Encéfalo/diagnóstico por imagem , Criatividade , Vias Neurais/patologia , Semântica , Adulto , Idoso , Análise de Variância , Sinais (Psicologia) , Feminino , Hemorragia/diagnóstico por imagem , Hemorragia/patologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Vias Neurais/diagnóstico por imagem , Testes Neuropsicológicos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Adulto JovemRESUMO
SEE BURGESS DOI101093/BRAIN/AWW092 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE : Analogical reasoning is at the core of the generalization and abstraction processes that enable concept formation and creativity. The impact of neurological diseases on analogical reasoning is poorly known, despite its importance in everyday life and in society. Neuroimaging studies of healthy subjects and the few studies that have been performed on patients have highlighted the importance of the prefrontal cortex in analogical reasoning. However, the critical cerebral bases for analogical reasoning deficits remain elusive. In the current study, we examined analogical reasoning abilities in 27 patients with focal damage in the frontal lobes and performed voxel-based lesion-behaviour mapping and tractography analyses to investigate the structures critical for analogical reasoning. The findings revealed that damage to the left rostrolateral prefrontal region (or some of its long-range connections) specifically impaired the ability to reason by analogies. A short version of the analogy task predicted the existence of a left rostrolateral prefrontal lesion with good accuracy. Experimental manipulations of the analogy tasks suggested that this region plays a role in relational matching or integration. The current lesion approach demonstrated that the left rostrolateral prefrontal region is a critical node in the analogy network. Our results also suggested that analogy tasks should be translated to clinical practice to refine the neuropsychological assessment of patients with frontal lobe lesions.
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Mapeamento Encefálico , Lobo Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Pensamento/fisiologia , Adulto , Idoso , Estudos de Casos e Controles , Imagem de Tensor de Difusão , Dominância Cerebral/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto JovemRESUMO
BACKGROUND: Paradoxical embolism via a patent foramen ovale (PFO) has been suggested as a potential stroke mechanism. Combined CT venography and pulmonary angiography (CVPA) is a simple, validated and accurate technique to diagnose deep venous thrombosis (DVT) or pulmonary embolism (PE). We sought to assess the prevalence of DVT or PE among patients with PFO and cryptogenic stroke (CS) by CVPA. METHODS: Patients were identified retrospectively from a clinical registry of consecutive patients with stroke admitted to our Stroke Unit. The following criteria were required for inclusion in this study: CS, PFO identified by transthoracic echography using contrast medium and CVPA performed during the hospitalization following stroke. RESULTS: A total of 114 patients with PFO underwent a CVPA within 7 days (interquartile range 4-9) from stroke symptom onset. On cerebral imaging, 11% had multiple infarcts. CVPA documented deep vein thrombosis (DVT) in 10 patients (8.8%) and PE in 5 patients (4.4%), that is, a total of 12 patients with prevalence of 10.5% (95% CI 5.5-17.7). Patients with PE-DVT had higher
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Embolia Paradoxal/diagnóstico por imagem , Forame Oval Patente/complicações , Embolia Pulmonar/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Trombose Venosa/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Angiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Flebografia/métodos , Prevalência , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodosRESUMO
Body-worn sensors (BWS) could provide valuable information in the management of Parkinson's disease and support therapeutic decisions based on objective monitoring. To study this pivotal step and better understand how relevant information is extracted from BWS results and translated into treatment adaptation, eight neurologists examined eight virtual cases composed of basic patient profiles and their BWS monitoring results. Sixty-four interpretations of monitoring results and the subsequent therapeutic decisions were collected. Relationship between interrater agreements in the BWS reading and the severity of symptoms were analyzed via correlation studies. Logistic regression was used to identify associations between the BWS parameters and suggested treatment modifications. Interrater agreements were high and significantly associated with the BWS scores. Summarized BWS scores reflecting bradykinesia, dyskinesia, and tremor predicted the direction of treatment modifications. Our results suggest that monitoring information is robustly linked to treatment adaptation and pave the way to loop systems able to automatically propose treatment modifications from BWS recordings information.
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BACKGROUND: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. METHODS: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. RESULTS: Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aß42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. DISCUSSION: Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Amiloide/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/complicações , Hemorragia Cerebral/complicações , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Imageamento por Ressonância Magnética , Fenótipo , Estudos RetrospectivosRESUMO
We explored the resting state functional connectivity correlates of apathy assessed as a multidimensional construct, using behavioral metrics, in behavioral variant frontotemporal dementia (bvFTD). We recorded the behavior of 20 bvFTD patients and 16 healthy controls in a close-to-real-life situation including a free phase (FP-in which actions were self-initiated) and a guided phase (GP-in which initiation of actions was facilitated by external guidance). We investigated the activity time and walking episode features as quantifiers of apathy. We used the means ((FP + GP)/2) and the differences (FP-GP) calculated for these metrics as well as measures by questionnaires to extract apathy dimensions by factor analysis. We assessed two types of fMRI-based resting state connectivity measures (local activity and seed-based connectivity) and explored their relationship with extracted apathy dimensions. Apathy in bvFTD was associated with lower time spent in activity combined with walking episodes of higher frequency, lower acceleration and higher duration. Using these behavioral metrics and apathy measures by questionnaires, we disentangled two dimensions: the global reduction of goal-directed behaviors and the specific deficit of self-initiation. Global apathy was associated with lower resting state activity within prefrontal cortex and lower connectivity of salience network hubs while the decrease in self-initiation was related to increased connectivity of parietal default-mode network hubs. Through a novel dimensional approach, we dissociated the functional connectivity correlates of global apathy and self-initiation deficit. We discussed in particular the role of the modified connectivity of lateral parietal cortex in the volitional process.
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Demência Frontotemporal , Humanos , Demência Frontotemporal/complicações , Objetivos , Imageamento por Ressonância Magnética , Cognição , Lobo Parietal , EncéfaloRESUMO
BACKGROUND: Apathy is highly frequent in behavioral variant frontotemporal dementia (bvFTD). It is presumed to involve different pathophysiological mechanisms and neuroanatomical regions. OBJECTIVE: We explored the hypothesis that subgroups showing distinct profiles of apathy and distinct patterns of atrophy within frontal lobes could be disentangled in bvFTD. METHODS: Using data-driven clustering applied to 20 bvFTD patients, we isolated subgroups according to their profiles on the three subscales of the Dimensional Apathy Scale (DAS). We explored their apathy profiles and atrophy patterns. Apathy profiles were characterized through both subjective measures of apathy by questionnaires and measures including objective behavioral metrics. Atrophy patterns were obtained by voxel-based morphometry, contrasting each bvFTD subgroup with healthy controls (Nâ=â16). RESULTS: By clustering based on DAS dimensions, we disentangled three subgroups of bvFTD patients, with distinct apathy profiles and atrophy patterns. One subgroup, which presented the smallest pattern of atrophy (including orbitofrontal cortex) with a right asymmetry, was characterized by high self-reported emotional and initiation apathy and by a self-initiation deficit reversible by external guidance. In other subgroups showing more diffuse bilateral atrophies extending to lateral prefrontal cortex, apathy was not reversible by external guidance and more difficulty to focus on goal-management was observed, especially in the subgroup with the largest atrophy and highest levels of executive apathy. CONCLUSION: Distinct clinical profiles of apathy, corresponding to distinct anatomical subtypes of bvFTD, were identified. These findings have implications for clinicians in a perspective of precision medicine as they could contribute to personalize treatments of apathy.
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Demência Frontotemporal , Humanos , Atrofia , Cognição/fisiologia , Lobo Frontal , Demência Frontotemporal/psicologia , Imageamento por Ressonância Magnética , Testes NeuropsicológicosRESUMO
Background Apathy is a common behavioral syndrome that occurs across neurological and psychiatric disorders. An influential theoretical framework defined apathy as the quantitative reduction of self-generated voluntary and purposeful behaviors. There is evidence in the literature of the multidimensional nature of apathy with cognitive, behavioral, and emotional dimensions. To date, apathy has been assessed using various scales and questionnaires. Alternative objective and ecological measurements of apathy are needed. New method We used the ECOCAPTURE protocol and an ethological approach to investigate behavior in bvFTD patients under ecological conditions (a waiting room) while they freely explored a novel environment. Data were collected by behavioral coding from 7-minute video using an ethogram and transformed into behavior time series data. We present an approach considering behavioral kinetics to assess behavior. We aimed to construct a new behavior analysis method, called ECOCAPTURE kinetics, using temporal classification for behavior time series data analysis. To develop our classifier, we retained a nonelastic Euclidian metric, combined with a convolutional approach. Results We applied the ECOCAPTURE kinetics method to a cohort of 20 bvFTD patients and 18 healthy controls. We showed that bvFTD patients can be classified according to their behavioral kinetics into three groups. Each subgroup was characterized by specific behavior disorders and neuropsychological profile. Comparison with Existing Method(s) The ECOCAPTURE kinetics method is different from those of the classical approach of measuring behavior, producing time budgets, frequency of behavior occurrences, or kinematic diagrams. Conclusions This approach can be extended to any behavioral study encoding time.
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Apatia , Demência Frontotemporal , Humanos , Testes Neuropsicológicos , Fatores de TempoRESUMO
INTRODUCTION: Paroxysmal movement disorders mostly comprise paroxysmal dyskinesia and episodic ataxia, and can be the consequence of a genetic disorder or symptomatic of an acquired disease. AREAS COVERED: In this review, the authors focused on certain hot-topic issues in the field: the respective contribution of the cerebellum and striatum to the generation of paroxysmal dyskinesia, the importance of striatal cAMP turnover in the pathogenesis of paroxysmal dyskinesia, the treatable causes of paroxysmal movement disorders not to be missed, with a special emphasis on the treatment strategy to bypass the glucose transport defect in paroxysmal movement disorders due to GLUT1 deficiency, and functional paroxysmal movement disorders. EXPERT OPINION: Treatment of genetic causes of paroxysmal movement disorders is evolving towards precision medicine with targeted gene-specific therapy. Alteration of the cerebellar output and modulation of the striatal cAMP turnover offer new perspectives for experimental therapeutics, at least for paroxysmal movement disorders due to selected causes. Further characterization of cell-specific molecular pathways or network dysfunctions that are critically involved in the pathogenesis of paroxysmal movement disorders will likely result in the identification of new biomarkers and testing of innovative-targeted therapeutics.
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Erros Inatos do Metabolismo dos Carboidratos , Coreia , Transtornos dos Movimentos , Ataxia , Humanos , Proteínas de Transporte de Monossacarídeos , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/terapia , MutaçãoRESUMO
INTRODUCTION: We aimed to investigate phenotypic heterogeneity in the behavioral variant of frontotemporal dementia (bvFTD) through assessment of inhibition deficits. METHODS: We assessed occurrences of 16 behavioral inhibition deficits from video recordings of 15 bvFTD patients (early stage) and 15 healthy controls (HC) in an ecological setting. We extracted dimensions of inhibition deficit and analyzed their correlations with cognitive and clinical measures. Using these dimensions, we isolated patient clusters whose atrophy patterns were explored. RESULTS: After identifying two patterns of inhibition deficit (compulsive automatic behaviors and socially unconventional behaviors), we isolated three behavioral clusters with distinct atrophy patterns. BvFTD-G0 (N = 3), an outlier group, showed severe behavioral disturbances and more severe ventromedial prefrontal cortex/orbitofrontal cortex atrophy. Compared to bvFTD-G1 (N = 6), bvFTD-G2 (N = 6) presented higher anxiety and depression along with less diffuse atrophy especially in midline regions. DISCUSSION: Identifying clinico-anatomical profiles through behavior observation could help to stratify bvFTD patients for adapted treatments.
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BACKGROUND: Neurophobia is a chronic disease of medical students and junior doctors. Early detection is needed to facilitate prevention and management as this fear can negatively impact patient care. METHODS: We conducted a two-part mono-centric study at the faculty of Medicine, Sorbonne University, in Paris. Part one: a cross-sectional study to validate a newly constructed neurophobia scale, NeuroQ. Part two: a prospective longitudinal study to assess the impact of The Move on student neurophobia using NeuroQ. A population-based sample of second-year medical students of the 2019 and 2020 class of the Faculty of Medicine of Sorbonne University were invited to participate. RESULTS: NeuroQ incorporates the main themes of the neurophobia definition and demonstrates uni-dimensionality. Three hundred and ninety-five medical students participated in the study (mean age was 20.0 years, SD: 2.1 years) assessing the effect of The Move teaching on neurophobia. Two hundred and eighty-eight (72.9%) students were female. After the Move teaching the mean NeuroQ score was significantly lower compared to the baseline NeuroQ score (mean [SD] variation, -1.1 [2.6], p < 0.001). There was a 22.3% relative reduction in the number of neurophobic students after The Move teaching. CONCLUSION: Our results highlight the utility of NeuroQ in assessing (i) baseline neurophobia and (ii) the impact of pre-clinical educational interventions on neurophobia. Furthermore, we have shown the importance of pre-clinical educational interventions, such as The Move, in tackling neurophobia.
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Neurologia , Estudantes de Medicina , Adulto , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson's disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson's disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
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Apathy is one of the six clinical criteria for the behavioral variant of frontotemporal dementia (bvFTD), and it is almost universal in this disease. Although its consequences in everyday life are debilitating, its underlying mechanisms are poorly known, its assessment is biased by subjectivity and its care management is very limited. In this context, we have developed "ECOCAPTURE," a method aimed at providing quantifiable and objective signature(s) of apathy in order to assess it and identify its precise underlying mechanisms. ECOCAPTURE consists of the observation and recording of the patient's behavior when the participant is being submitted to a multiple-phase scenario reproducing a brief real-life situation. It is performed in a functional exploration platform transformed into a fully furnished waiting room equipped with a video and sensor-based data acquisition system. This multimodal method allowed video-based behavior analyses according to predefined behavioral categories (exploration behavior, sustained activities or inactivity) and actigraphy analyses from a 3D accelerometer. The data obtained were also correlated with behavioral/cognitive tests and scales assessing global cognitive efficiency, apathy, cognitive disinhibition, frontal syndrome, depression and anxiety. Here, bvFTD patients (n = 14) were compared to healthy participants (n = 14) during the very first minutes of the scenario, when the participants discovered the room and were encouraged to explore it. We showed that, in the context of facing a new environment, healthy participants first explored it and then engaged in sustained activities. By contrast, bvFTD patients were mostly inactive and eventually explored this new place, but in a more irregular and less efficient mode than normal subjects. This exploration deficit was correlated with apathy, disinhibition and cognitive and behavioral dysexecutive syndromes. These findings led us to discuss the presumed underlying mechanisms responsible for the exploration deficit (an inability to self-initiate actions, to integrate reward valuation and to inhibit involuntary behavior). Altogether, these results pave the way for simple and objective assessment of behavioral changes that represents a critical step for the evaluation of disease progression and efficacy of treatment in bvFTD.
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For complex mental functions such as creative thinking, inter-individual variability is useful to better understand the underlying cognitive components and brain anatomy. Associative theories propose that creative individuals have flexible semantic associations, which allows remote elements to be formed into new combinations. However, the structural brain variability associated with the ability to combine remote associates has not been explored. To address this question, we performed a voxel-based morphometry (VBM) study and explored the anatomical connectivity of significant regions. We developed a Remote Combination Association Task adapted from Mednick's test, in which subjects had to find a solution word related to three cue words presented to them. In our adaptation of the task, we used free association norms to quantify the associative distance between the cue words and solution words, and we varied this distance. The tendency to solve the task with insight and the ability to evaluate the appropriateness of a proposed solution were also analysed. Fifty-four healthy volunteers performed this task and underwent a structural MRI. Structure-function relationships were analysed using regression models between grey matter (GM) volume and task performance. Significant clusters were mapped onto an atlas of white matter (WM) tracts. The ability to solve the task, which depended on the associative distance of the solution word, was associated with structural variation in the left rostrolateral prefrontal and posterior parietal regions; the left rostral prefrontal region was connected to distant regions through long-range pathways. By using a creative combination task in which the semantic distance between words varied, we revealed a brain network centred on the left frontal pole that appears to support the ability to combine information in new ways by bridging the semantic distance between pieces of information.